This is a national stage application of International Application PCT/EP00/12743, filed Dec. 14, 2000, which was published under PCT Article 21(2) as PCT Publication No. WO 01/46156 in English, and which claims the benefit of International Application PCT/EP99/10276 filed Dec. 22, 1999. Both International Applications PCT/EP00/12743 and PCT/EP99/10276 are hereby incorporated by reference in their entireties.
The present invention relates to novel butyne diol derivatives of the general formula I and their use as active ingredients in the preparation of pharmaceutical compositions. The invention also concerns related aspects including processes for the preparation of the compounds, pharmaceutical compositions containing one or more compounds of the general formula I and especially their use as endothelin receptor antagonists.
Endothelins (ET-1, ET-2, and ET-3) are 21-amino acid peptides produced and active in almost all tissues (Yanagisawa M et al.: Nature (1988) 332:411. Endothelins are potent vasoconstrictors and important mediators of cardiac, renal, endocrine and immune functions (McMillen M A et al.: J Am Coll Surg (1995) 180:621). They participate in bronchoconstriction and regulate neurotransmitter release, activation of inflammatory cells, fibrosis, cell proliferation and cell differentiation (Rubanyi G M et al.: Pharmacol Rev (1994) 46:328).
Two endothelin receptors have been cloned and characterized in mammals (ETA, ETB) (Arai H et al.: Nature (1990) 348:730; Sakurai T et al.: Nature (1990) 348:732). The ETA receptor is characterized by higher affinity for ET-1 and ET-2 than for ET-3. It is predominant in vascular smooth muscle cells and mediates vasoconstricting and proliferative responses (Ohlstein E H et al.: Drug Dev Res (1993) 29:108). In contrast, the ETB receptor has equivalent affinity for the 3 endothelin isopeptides and binds the linear form of endothelin, tetra-ala-endothelin, and sarafotoxin S6C (Ogawa Y et al.: BBRC (1991) 178:248). This receptor is located in the vascular endothelium and smooth muscles, and is also particularly abundant in lung and brain. The ETB receptor from endothelial cells mediates transient vasodilator responses to ET-1 and ET-3 through the release of nitric oxide and/or prostacyclin whereas the ETB receptor from smooth muscle cells exerts vasoconstricting actions (Sumner M J et al.: Brit J Pharmacol (1992) 107:858). ETA and ETB receptors are highly similar in structure and belong to the superfamily of G-protein coupled receptors.
A pathophysiological role has been suggested for ET-1 in view of its increased plasma and tissue levels in several disease states such as hypertension, sepsis, atherosclerosis, acute myocardial infarction, congestive heart failure, renal failure, migraine and asthma. As a consequence, endothelin receptor antagonists have been studied extensively as potential therapeutic agents. Endothelin receptor antagonists have demonstrated preclinical and/or clinical efficacy in various diseases such as cerebral vasospasm following subarachnoid hemorrhage, heart failure, pulmonary and systemic hypertension, neurogenic inflammation, renal failure and myocardial infarction.
Today, no endothelin receptor antagonist is marketed yet, several are in clinical trials. However, these molecules possess a number of weaknesses such as complex synthesis, low solubility, high molecular weight, poor pharmacokinetics or safety problems (e.g. liver enzyme increases). Furthermore, the contribution of differential ETA/ETB receptor blockade to the clinical outcome is not known. Thus, tailoring of the physicochemical, pharmacokinetic properties and the selectivity profile of each antagonist for a given clinical indication is mandatory. We have discovered a new class of butyne-diol derivatives of the structure below and found that they allow the specific tailoring described above.
The inhibitory activity of the compounds of formula I on endothelin receptors can be demonstrated using the test procedures described hereinafter:
For the evaluation of the potency and efficacy of the compounds of the general formula I the following tests were used:
1) Inhibition of Endothelin Binding to Membranes from CHO Cells Carrying Human ET Receptors:
For competition binding studies, membranes of CHO cells expressing human recombinant ETA or ETB receptors were used. Microsomal membranes from recombinant CHO cells were prepared and the binding assay made as previously described (Breu et al, FEBS Lett 1993; 334:210).
The assay was performed in 200 uL 50 mM Tris/HCl buffer, pH 7.4, including 25 mM MnCl2, 1 mM EDTA and 0.5% (w/v) BSA in polypropylene microtiter plates. Membranes containing 0.5 ug protein were incubated for 2 h at 20xc2x0 C. with 8 pM [125I]ET-1 (4000 cpm) and increasing concentrations of unlabelled antagonists. Maximum and minimum binding were estimated in samples without and with 100 nM ET-1, respectively. After two h, the membranes were filtered on filterplates containing GF/C filters (Unifilterplates from Canberra Packard S.A. Zxc3xcrich, Switzerland). To each well, 50 uL of scintillation cocktail was added (MicroScint 20, Canberra Packard S.A. Zxc3xcrich, Switzerland) and the filter plates counted in a microplate counter (TopCount, Canberra Packard S.A. Zxc3xcrich, Switzerland).
All the test compounds were dissolved, diluted and added in DMSO. The assay was run in the presence of 2.5% DMSO which was found not to interfere significantly with the binding. IC50 was calculated as the concentration of antagonist inhibiting 50% of the specific binding of ET-1. For reference compounds, the following IC50 values were found: ETA cells: 0.075 nM (n=8) for ET-1 and 118 nM (n=8) for ET-3; ETB cells: 0.067 nM (n=8) for ET-1 and 0.092 nM (n=3) for ET-3.
The IC50 values obtained with compounds of formula I are given in Table 1
2) Inhibition of Endothelin-induced Contractions on Isolated Rat Aortic Rings (ETA Receptors) and Rat Tracheal Rings (ETB Receptors)
The functional inhibitory potency of the endothelin antagonists was assessed by their inhibition of the contraction induced by endothelin-1 on rat aortic rings (ETA receptors) and of the contraction induced by sarafotoxin S6c on rat tracheal (ETB receptors). Adult Wistar rats were anesthetized and exsanguinated. The thoracic aorta or trachea were excised, dissected and cut in 3-5 mm rings. The endothelium/epithelium was removed by gentle rubbing of the intimal surface. Each ring was suspended in a 10 ml isolated organ bath filled with Krebs-Henseleit solution (in mM; NaCl 115, KCl 4.7, MgSO4 1.2, KH2PO4 1.5, NaHCO3 25, CaCl2 2.5, glucose 10) keep at 37xc2x0 C. and gassed with 95% O2 and 5% CO2. The rings were connected to force transducers and isometric tension was recorded (EMKA Technologies SA, Paris, France). The rings were stretched to a resting tension of 3 g (aorta) or 2 g (trachea). Cumulative doses of ET-1 (aorta) or sarafotoxin S6c (trachea) were added after a 10 min incubation with the test compound or its vehicle. The functional inhibitory potency of the test compound was assessed by calculating the concentration ratio, i.e. the shift to the right of the EC50 induced by different concentrations of test compound. EC50 is the concentration of endothelin needed to get a half-maximal contraction, pA2 is the negative logarithm of the antagonist concentration which induces a two-fold shift in the EC50 value.
The pA2 values obtained with compounds of formula I are given in Table 2.
Because of their ability to inhibit the endothelin binding, the described compounds can be used for treatment of diseases which are associated with an increase in vasoconstriction, proliferation or inflammation due to endothelin. Examples of such diseases are hypertension, coronary diseases, cardiac insufficiency, renal and myocardial ischemia, renal failure, cerebral ischemia, dementia, migraine, subarachnoidal hemorrhage, Raynaud""s syndrome, portal hypertension and pulmonary hypertension. They can also be used for atherosclerosis, prevention of restenosis after balloon or stent angioplasty, inflammation, stomach and duodenal ulcer, cancer, prostatic hypertrophy, erectile dysfunction, hearing loss, amaurosis, chronic bronchitis, asthma, gram negative septicemia, shock, sickle cell anemia, glomerulonephritis, renal colic, glaucoma, therapy and prophylaxis of diabetic complications, complications of vascular or cardiac surgery or after organ transplantation, complications of cyclosporin treatment, as well as other diseases presently known to be related to endothelin.
The compounds can be administered orally, rectally, parenterally, e.g. intravenously, intramuscularly, subcutaneously, intrathecally or transdermally; or sublingually or as ophthalmic preparation or administered as aerosol. Examples of applications are capsules, tablets, oral administered suspensions or solutions, suppositories, injections, eye-drops, ointments or aerosols/nebulizers.
Preferred applications are intravenous, intra-muscular, eye drops or oral administrations. The dosage used depends upon the type of the specific active ingredient, the age and the requirements of the patient and the kind of application. Generally, dosages of 0.1-50 mg/kg body weight per day are considered. The preparations with compounds can contain inert or as well pharmacodynamically active excipients. Tablets or granules, for example, could contain a number of binding agents, filling excipients, carrier substances or diluents.
In the Patent Specifications EP 743307 and EP 882719 related endothelin receptor antagonists are disclosed. However, only in EP 882719 in Table 1 IC50 values for the ETA receptor are given. The corresponding values of the instantly claimed compounds are in a head-to-head comparison much better and also much more specific, since one can differentiate between activity of both receptors and can also prepare mixed antagonists.
The present invention relates to butyne diol derivatives of the general formula I, 
wherein
R1 represents phenyl; mono-, di- or tri-substituted phenyl substituted with halogen, lower alkyl, lower alkenyl, lower alkynyl, lower alkoxy, hydroxy-lower alkyl, hydroxy-lower alkenyl, hydroxy-lower alkynyl, trifluoromethyl, cycloalkyl, hydroxy-cycloalkyl; 2-pyridyl; 5-substituted 2-pyridyl substituted with lower alkyl, five membered heteroaryl rings containing one or two nitrogen, sulfur or oxygen atoms;
R2 represents hydrogen; lower alkyl; phenyl; mono-, di- or tri-substituted phenyl substituted with halogen, lower alkyl, lower alkoxy, lower alkyloxy-lower alkyl, trifluoromethyl, five membered heteroaryl rings containing one or two nitrogen, sulfur or oxygen atoms which may be mono- or di-substituted with halogen, lower alkyl, lower alkoxy; benzyl; mono- or di-substituted benzyl substituted with halogen, lower alkyl, lower alkoxy, trifluoromethyl, 2-pyrimidyl; mono- or di-substituted 2-pyrimidyl substituted with lower alkyl, lower alkoxy, halogen, trifluoromethyl, a group of the formula xe2x80x94C(A)xe2x80x94Bxe2x80x94Ra, wherein
A represents O or S;
B represents NH and
Ra represents lower alkyl; cycloalkyl; phenyl; mono-, di- or tri-substituted phenyl substituted with halogen, lower alkyl, lower alkenyl, lower alkoxy, trifluoromethyl, six membered heteroaryl rings containing one or two nitrogen atoms which may be mono-, di- or substituted with halogen, lower alkyl, lower akyloxy;
R3 represents phenyl; mono-, di- or tri-substituted phenyl substituted with lower alkyl, lower alkenyl, lower alkyloxy, trifluoromethyl, halogen, hydroxy;
R4 represents hydrogen, halogen, trifluoromethyl, lower alkyl, lower alkyloxy, lower alkylthio, lower alkyl-oxy-lower alkyl; phenyl; mono- or di-substituted phenyl substituted with halogen, lower alkyl, lower alkoxy, lower alkylen or lower alkenylen or lower alkylenoxy or lower alkylendioxy forming with the phenyl ring a five- or six-membered ring, heteroaryl; heterocyclyl;
X represents oxygen; sulfur; or a bond;
and pure enantiomers, enantiamerically pure diastereomers, mixtures of diastereomers, diastereomeric racemates, mixtures of diastereomeric racemates and pharmaceutically acceptable salts thereof.
In the definitions of the general formula Ixe2x80x94if not otherwise statedxe2x80x94the expression lower means straight and branched chain groups with one to seven carbon atoms, preferably 1 to 4 carbon atoms. Examples of lower alkyl and lower alkoxy groups are methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert.-butyl, pentyl, hexyl, heptyl, methoxy, ethoxy, propoxy, butoxy, iso-butoxy, sec-butoxy and tert.-butoxy. Lower alkylendioxy-groups are preferably methylen-dioxy, ethylen-dioxy, propylen-dioxy and butylen-dioxy-groups. Examples of lower alkanoyl-groups are acetyl, propanoyl and butanoyl. Lower alkenylen means e.g.vinylen, propenylen and butenylen. Lower alkenyl and lower alkynyl means groups like ethylen, propylen, butylen, tert.-butylen(2-methyl-propenyl), and acetylenyl, propinylen, butinylen, pentinylen, 2-methyl-pentinylen etc. Lower alkenyloxy means allyloxy, vinyloxy, propenyloxy and the like. The expression cycloalkyl means a saturated cyclic hydrocarbon ring with 3 to 6 carbon atoms, e.g. cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl which may be substituted with lower alkyl, hydroxy-lower alkyl, amino-lower alkyl, lower alkoxy-lower alkyl and lower alkenylen groups. The expression heterocyclyl means saturated or unsaturated (but not aromatic) five-, six- or seven-membered rings containing one or two nitrogen, oxygen or sulfur atoms which may be the same or different and which rings may be substituted with lower alkyl, amino, halogen, nitro, hydroxy, lower alkoxy, e.g. piperidinyl, morpholinyl, piperazinyl, tetrahydropyranyl, dihydropyranyl, 1,4-dioxanyl, pyrrolidinyl, tetrahydrofuranyl, dihydropyrrolyl, dihydroimidazolyl, dihydropyrazolyl, pyrazolidinyl etc. and substituted derivatives of such rings with substituents as outlined above. The expression heteroaryl means six-membered aromatic rings containing one to four nitrogen atoms, benzofused six-membered aromatic rings containing one to three nitrogen atoms, five-membered aromatic rings containing one oxygen or one nitrogen or one sulfur atom, benzo-fused five-membered aromatic rings containing one oxygen or one nitrogen or one sulfur atom, five membered aromatic rings containig an oxygen and nitrogen atom and benzo fused derivatives thereof, five membred aromatic rings containing a sulfur, nitrogen or oxygen atom and benzo fused derivatives thereof, five-membered aromatic rings containing two nitrogen atoms and benzo fused derivatives thereof, five membered aromatic rings containing three nitrogen atoms and benzo fused derivatives thereof or the tetrazolyl ring, e.g. furanyl, thienyl, pyrrolyl, pyridinyl, indolyl, quinolinyl, isoquinolinyl, imidazolyl, triazinyl, thiazinyl, pyridazinyl, oxazolyl, etc. whereby such rings may be substituted with lower alkyl, amino, amino-lower alkyl, halogen, hydroxy, lower alkoxy or trifluoromethyl. The expression aryl represents mono-, di- or tri-substituted aromatic rings with 6 to 10 carbon atoms like phenyl or naphthyl rings which may be substituted with phenyl, halogen, hydroxy, lower alkoxy, lower alkyl, trifluoromethyl, lower alkenyloxy, trifluoromethoxy, cyclopropyl, hydroxy-cyclopropyl, lower alkylenoxy or lower alkylendioxy.
The expression pharmaceutically acceptable salts encompasses either salts with inorganic acids or organic acids like hydrohalogenic acids, e.g. hydrochloric or hydrobromic acid; sulfuric acid, phosphoric acid, nitric acid, citric acid, formic acid, acetic acid, maleic acid, tartaric acid, methylsulfonic acid, p-toluolsulfonic acid and the like or in case the compound of formula I is acidic in nature with an inorganic base like an alkali or earth alkali base, e.g. sodium hydroxide, potassium hydroxide, calcium hydroxide etc.
The compounds of the general formula I might have one or more asymmetric carbon atoms and may be prepared in form of optically pure enantiomers or diastereomers, mixtures of enantiomers or diastereomers, diastereomeric racemates, mixtures of diastereomeric racemates. The present invention encompasses all these forms. Mixtures may be separated in a manner known per se, i.e. by column chromatography, thin layer chromatography, HPLC, crystallization etc.
Because of their ability to inhibit the endothelin binding, the described compounds of the general formula I and their pharmaceutically acceptable salts may be used for treatment of diseases which are associated with an increase in vasoconstriction, proliferation or inflammation due to endothelin. Examples of such diseases are hypertension, coronary diseases, cardiac insufficiency, renal and myocardial ischemia, renal failure, cerebral ischemia, dementia, migraine, subarachnoidal hemorrhage, Raynaud""s syndrome, portal hypertension and pulmonary hypertension. They can also be used for atherosclerosis, prevention of restenosis after balloon or stent angioplasty, inflammation, stomach and duodenal ulcer, cancer, prostatic hypertrophy, erectile dysfunction, hearing loss, amaurosis, chronic bronchitis, asthma, gram negative septicemia, shock, sickle cell anemia, glomerulonephritis, renal colic, glaucoma, therapy and prophylaxis of diabetic complications, complications of vascular or cardiac surgery or after organ transplantation, complications of cyclosporin treatment, as well as other diseases presently known to be related to endothelin.
These compositions may be administered in enteral or oral form e.g. as tablets, dragees, gelatine capsules, emulsions, solutions or suspensions, in nasal form like sprays or rectically in form of suppositories. These compounds may also be administered in intramuscular, parenteral or intraveneous form, e.g. in form of injectable solutions.
These pharmaceutical compositions may contain the compounds of formula I as well as their pharmaceutically acceptable salts in combination with inorganic and/or organic excipients which are usual in the pharmaceutical industry like lactose, maize or derivatives thereof, talcum, stearinic acid or salts of these materials.
For gelatine capsules vegetable oils, waxes, fats, liquid or half-liquid polyols etc. may be used. For the preparation of solutions and sirups e.g. water, polyols, saccharose, glucose etc. are used. Injectables are prepared by using e.g. water, polyols, alcohols, glycerin, vegetable oils, lecithin, liposomes etc. Suppositories are prepared by using natural or hydrogenated oils, waxes, fatty acids (fats), liquid or half-liquid polyols etc.
The compositions may contain in addition preservatives, stabilisation improving substances, viscosity improving or regulating substances, solubility improving substances, sweeteners, dyes, taste improving compounds, salts to change the osmotic pressure, buffer, antioxidants etc.
The compounds of formula I may also be used in combination with one or more other therapeutically useful substances e.g. xcex1- and xcex2-blockers like Phentolamine, Phenoxybenzamine, Atenolol, Propranolol, Timolol, Metoprolol, Carteolol etc.; Vasodilators like Hydralazine, Minoxidil, Diazoxide, Flosequinan etc.; Calcium-antagonists like Diltiazem, Nicardipine, Nimodipine, Verapamil, Nifedipine etc.; ACE-inhibitors like Cilazapril, Captopril, Enalapril, Lisinopril etc.; Potassium activators like Pinacidil etc. Angiotensin II antagonists; Diuretics like Hydrochlorothiazide, Chlorothiazide, Acetolamide, Bumetamide, Furosemide, Metolazone, Chlortalidone etc.; Sympatholitics like Methyldopa, Clonidine, Guanabenz, Reserpine etc.; and other therapeutics which serve to treat high blood pressure or any cardiac disorders.
The dosage may vary within wide limits but should be adapted to the specific situation. In general the dosage given in oral form should daily be between about 3 mg and about 3 g, preferably between about 10 mg and about 1 g, especially preferred between 5 mg and 300 mg, per adult with a body weight of about 70 kg. The dosage should be administered preferably in 1 to 3 doses per day which are of equal weight. As usual children should receive lower doses which are adapted to body weight and age.
A preferred group of compounds are compounds of formula I wherein R1, R2, and R4 are as defined above, and wherein
R3 represents phenyl; mono substituted phenyl substituted with lower alkyl, lower alkyloxy, trifluoromethyl, halogen;
X represents oxygen or a single bond,
and pharmaceutically acceptable salts thereof.
Another preferred group of compounds are compounds of formula II 
wherein R2, R3, R4, and X are as defined in formula I above, and R5 represents lower alkyl,
and pharmaceutically acceptable salts of compounds of formula II.
Another group of preferred compounds are compounds of formula III 
wherein R1, R3, R4, and X are as defined in formula I above, and R6, R7, and R8, each and independently represents hydrogen, lower alkyl, lower alkyloxy, halogen, trifluoromethyl;
and pharmaceutically acceptable salts thereof.
Yet another group of preferred compounds are compounds of formula IV 
wherein R1, R3, R4, Ra and X are as defined in formula I above,
and pharmaceutically acceptable salts thereof.
Another group of preferred compounds are compounds of formula I wherein R1, R3, R4, and X are as defined in formula I above, and wherein R2 represents lower alkyl,
and pharmaceutically acceptable salts thereof.
Another group of preferred compounds are the compounds given below:
5-isopropyl-N-[6-(4-hydroxy-2-butynyloxy)-5-(o-methoxyphenoxy)-2-(4-pyridyl)-4-pyrimidinyl]-2-pyridine sulfonamide;
4-tert.-butyl-N-[6-(4-hydroxy-2-butynyloxy)-5-(o-methoxyphenoxy)-2-(4-pyridyl)-4-pyrimidinyl]-benzene sulfonamide;
5-methyl-N-[6-(4-hydroxy-2-butynyloxy)-5-(o-methoxyphenoxy)-2-(4-pyridyl)-4-pyrimidinyl]-2-pyridine sulfonamide;
5-isopropyl-N-[6-chloro-5-(o-methoxyphenoxy)-2-(2-pyrimidinyl)-4-pyrimidinyl]-2-pyridine sulfonamide;
4-tert.-butyl-N-[6-chloro-5-(o-methoxyphenoxy)-2-(2-pyrimidinyl)-4-pyrimidinyl]benzene sulfonamide;
5-isopropyl-N-[6-(4-hydroxy-2-butynyloxy)-5-(o-methoxyphenoxy)-2-(N-morpholino)-4-pyrimidinyl]-2-pyridine sulfonamide;
5-isopropyl-N-[6-(4-hydroxy-2-butynyloxy)-5-(p-tolyl)-2-(4-pyridyl)-4-pyrimidinyl]-2-pyridine sulfonamide;
5-isopropyl-N-[6-(4-(4,6-dimethoxy-2-pyrimidinyloxy)-2-butynyloxy)-5-(o-methoxyphenoxy)-2-(4-pyridyl)-4-pyrimidinyl]-2-pyridine sulfonamide;
4-tert.-butyl-N-[6-(4-(2-pyrimidinyloxy)-2-butynyloxy)-5-(o-methoxyphenoxy)-2-(4-pyridyl)-4-pyrimidi-nyl]-benzene sulfonamide;
4-tert.-butyl-N-[6-(4-(4,6-dimethoxy-2-pyrimidinyloxy)-2-butynyloxy)-5-(o-methoxyphenoxy)-2-(4-pyridyl)-4-pyrimidinyl]-benzene sulfonamide;
2-pyridinyl-carbamic acid 4-[6-(5-isopropyl-pyridine-2-sulfonylamino)-5-(2-methoxy-phenoxy)-2-pyridin-4-yl-pyrimidin-4-yloxy]-but-2-ynyl ester;
phenyl-carbamic acid 4-[6-(5-isopropyl-pyridine-2-sulfonylamino)-5-(2-methoxy-phenoxy)-2-methyl-pyrimidin-4-yloxy]-but-2-ynyl ester;
phenyl-carbamic acid 4-[6-(5-isopropyl-pyridine-2-sulfonylamino)-5-(2-methoxy-phenoxy)-2-morpholin-4-yl-pyrimidin-4-yloxy]-but-2-ynyl ester;
2-pyridinyl-carbamic acid 4-[6-(5-isopropyl-pyridine-2-sulfonylamino)-5-(2-methoxy-phenoxy)-2-(N-morpholino)-pyrimidin-4-yloxy]-but-2-ynyl ester;
2-pyridinyl-carbamic acid 4-[6-(5-methyl-pyridine-2-sulfonylamino)-5-(2-methoxy-phenoxy)-2-(4-morpholino)-pyrimidin-4-yloxy]-but-2-ynyl ester;
4-pyrazinyl-carbamic acid 4-[6-(5-methyl-pyridine-2-sulfonylamino)-5-(2-methoxy-phenoxy)-2-(4-morpholino)-pyrimidin-4-yloxy]-but-2-ynyl ester;
4-tert.-butyl-N-[6-(4-methoxy-2-butynyloxy)-5-(o-methoxy-phenoxy)-2-(2-pyrimidinyl)-4-pyrimidinyl]benzene sulfonamide;
5-isopropyl-N-[6-(4-methoxy-2-butynyloxy)-5-(o-methoxyphenoxy)-2-(N-morpholino)-4-pyrimidinyl]-2-pyridine sulfonamide;
and pharmaceutically acceptable salts thereof.
The compounds of the general formula I are prepared from compounds of the formula V by one of the two pathways given below. The compounds VI are reacted either with a compound R2xe2x80x94Y, where Y represents a reactive leaving group such as chlorine, bromine, a sulfone, a sulfate, etc., or, in the case where R2 represents a group of the formula C(A)xe2x80x94NHxe2x80x94Ra, with a compound Raxe2x80x94Nxe2x95x90Cxe2x95x90A where Ra and A are as defined in the general formula I. Compounds of the formula VII can be prepared by reacting 2-butyne-1,4-diol with R2xe2x80x94Y in the presence of a base (e.g. an alkali metal hydroxide, an alkali metal alkoxide, sodium hydride, etc.) in a solvent such as DMSO, DMF, THF, pyridine, water, etc. (e.g. Tetrahedron Letters 38 (1997), 7887-7890; Bull. Chem. Soc. Jpn. 28 (1955), 80-82; J. Org. Chem. 18 (1953), 1601-1606). Compounds of the formula VII can also be prepared by reacting a suitably hydroxy-protected 1-chloro-4-hydroxy-2-butyne with an alkoxide, followed by cleavage of the protecting group as described in the literature (e.g. Bull. Chim. Soc. 1955, 502; J. Org. Chem. USSR (Engl. Transl.) 12 (1976), 505-507; J. Org. Chem. 63 (1998), 4291-4298). 
Compounds V are prepared from the corresponding dichloro compounds VIII (Bioorg. Med. Chem. Letters 7 (1997), 2223-2228, Chimia 50 (1996), 519-524, and references cited therein). 
Treatment of VIII with an excess of the appropiate sulfonamide potassium salt in the presence or absence of a base (e.g. triethylamine, Hxc3xcnig""s base) in a solvent (e.g DMF, DMSO) at room temperature furnished the desired compounds V. The sulfonamide potassiums salts may be prepared according to e.g. Bioorg. Med. Chem. Letters 7 (1997), 2223-2228.
Compounds VIII could be prepared by treating the corresponding compounds IX (or tautomeric forms thereof) at elevated temperatures (30-120xc2x0 C.) with a chlorinating agent such as POCl3, PCl5, or mixtures thereof, etc. each in the presence or absence of a base such as N,N-dialkylaniline or benzyltriethyl ammoniumchloride (e.g. Bioorg. Med. Chem. Lett., 7 (1997), 2223-2228; J. Med. Chem., 41 (1998), 3793-3803; J. Chem. Soc. 1959, 2214; Bull. Soc. Chim. Fr. 1959, 741-742). 
In a standard method as described by Pinner (for review see e.g. The Pyrimidines, by D. J. Brown, Wiley Interscience, New York 1970), the compounds IX resulted from condensation of the corresponding amidines X (isolated as hydrochloride salts) with the appropriate malonic ester derivatives XI in the presence of a sodium alkoxide in a solvent such as methanol, ethanol, etc. at room temperature (e.g. Bull. Soc. Chim. Fr. 1960, 1648). 
The amidines X were prepared form the corresponding nitrites XII by treatment of the nitriles XII either with sodium methylate in methanol followed by the addition of ammoniumchloride, or with lithium hexamethyldisilazan followed by the addition of hydrochloric acid in isopropanol (Advanced Organic Chemistry, by J. March, 3rd edtion, Wiley 1985, p. 803 and references cited therein). 
The malonic ester derivatives XI were either commercially available or were prepared following the procedures found in the literature (e.g. J. Am. Chem. Soc. 62 (1940), 1154, 1155; ibid. 74 (1952), 4466; J. Chem. Soc. Perkin 1, 1979, 2382-2386; Collect. Czech. Chem. Comm. 55 (1990), 1278-1289; J. Med. Chem. Chim. Ther. 26 (1991), 599-604; Bull. Soc. Chim. Fr. 1973, 2065-2071).
As the case may be, compounds with one or more optically active carbon atom are resolved into pure enantiomers or diastereomers, mixtures of enantiomers or diastereomers, diastereomeric racemates, mixtures of diastereomeric racemates in a manner known per se, and, if desired, synthesised compounds of formula I were converted into a pharmaceutically acceptable salt in a manner known per se.